New Report Questions Safety of Hepatitis C Drugs

Liver failure could also be associated with the new direct-acting antivirals.

A new report from the Institute of Safe Medication Practices (ISMP) warned that liver failure might be associated with the new direct-acting antiviral (DAA) agents. The statement followed the recent US Food and Drug Administration (FDA) advisory on hepatitis B reactivation associated with hepatitis C treatment.

The report acknowledged that the new agents represent the kind of therapeutic advance that the FDA characterizes as "breakthrough." However, the report also pointed out that in reducing the required clinical testing from 24 to 12 weeks, the agency could have missed cases of deterioration occurring after the primary efficacy end-point of sustained virologic response (SVR).

"The FDA and pharmaceutical companies were also overoptimistic in labeling as a "cure" the results of a laboratory assay at 12 weeks indicating undetectable levels of the hepatitis C virus genotype," the report said.

The ISMP initiated its investigation of liver failure in patients receiving DAAs after noting that three of the 24 cases involved in the October 2016 advisory on the reactivation of hepatitis B had experienced liver failure. Two had died and one received a liver transplant.

In searching the FDA Adverse Event Reporting System (FAERS) for reports filed in the 12 months ending June 30, 2016, the ISMP found 524 cases of liver failure in which one of the nine DAAs was a primary or secondary suspect drug. It also identified 1,058 cases of severe liver damage that had not progressed to liver failure.

Since the adverse event reports didn’t include medical history, the ISMP wasn't able to discern whether cases of liver failure reflected adverse drug reaction or progression of the underlying disease.

However, according to the ISMP, "90% of cases were reported by healthcare professionals as a drug-related adverse event and not the natural progression of hepatitis C."

In addition, the ISMP noted that while liver failure in patients receiving a DAA could reflect an advanced or aggressive disease state, it also marked that "the drugs failed to work”. The ISMP discovered 761 cases in the DAA clinical trials in which the outcome was described as "Drug Ineffective." Seventeen of these were included in the 524 cases that progressed to liver failure.

"This form of treatment failure is consequential, given that the patient is exposed to the risk and expense of treatment, and the drugs are sometimes used in patients starting to suffer clinical complications of hepatitis C with limited options available," the ISMP reported.

Although the report did not contain a response from the FDA, the agency has described its rationale for reducing the duration of clinical testing of the DAAs within a draft guidance for industry issued in May.

"In brief, there was a high rate of concordance between SVR12 and SVR24 in more than 13,000 patients pooled from multiple clinical trials of peg-IFN-based regimens," the draft guidance explained.

The report did convey the response from Gilead Sciences, the manufacturer of sofosbuvir (Solvaldi) and ledipasvir-sofosbuvir (Harvoni), that it had "seen no evidence of a causal relationship between sofosbuvir-based regiments and liver failure."

The report also highlighted that Gilead did recognize that the drug was not 100% effective, and could be the likely cause of liver failure to disease relapse rather than adverse drug reaction. Janssen, the manufacturer of simeprevir (Olysio), also responded to the ISMP indicating, “The drug's adverse event profile was consistent with those seen in clinical trials and reflected in the prescribing information."

The ISMP report concluded with a call for further investigation, "While direct-acting antivirals should be classified as a major advance, important questions remain unanswered about their long-term effects and appropriate patient population."

"A better understanding of what is occurring in hundreds of additional liver failure cases should be a priority for further investigation," the report declared.

The ISMP report, “New Safety Issues for Hepatitis C Antivirals,” was issued on January 25 as part of its quarterly report on monitoring of FDA Medwatch.

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